Kunitz type protease inhibitor from the canine tapeworm as a potential therapeutic for melanoma

Abstract

Modulating the tumor microenvironment to promote an effective immune response is critical in managing any type of tumor. Melanoma is an aggressive skin cancer and the incidence rate is increasing worldwide. Potent protease inhibitors have recently been extensively researched as potential therapeutic agents against various cancers. EgKI-1 is a potent Kunitz type protease inhibitor identified from the canine tapeworm Echinococcus granulosus that has shown anti-cancer activities in vivo. In this study we show that EgKI-1 significantly reduced the growth of melanoma in the B16-F0 mouse model and was not toxic to normal surrounding tissue. Moreover, EgKI-1 treatment significantly reduced survivin expression levels and increased the CD8+ T cell population in draining axillary lymph nodes. Therefore, EgKI-1 potentially reduces tumor growth by inducing apoptosis and modulating the tumor microenvironment, and has potential for development as an intra-lesional treatment for melanoma.

Schistosome Infection and Schistosome-Derived Products as Modulators for the Prevention and Alleviation of Immunological Disorders

“…Indeed, S. haematobium is a Group-1 carcinogen and, alarmingly, is the leading cause of bladder cancer globally ( 124 ). On the other hand, there is growing evidence showing that parasite infection or parasite-derived products can also reduce cancer tumorigenesis through the induction of apoptosis, activation of the immune response, avoidance of metastasis and angiogenesis ( 125 , 126 ). For the first time, S. mansoni was reported recently to have a therapeutic effect on murine colon cancer ( 57 ).…”

“…In-depth transcriptomic and proteomic analysis of the different schistosome species and/or different developmental stages, such as egg secretome studies which have led to the discovery of highly sensitive antigens for the diagnosis of schistosomiasis ( 131 – 135 ) may facilitate the identification of additional molecules with therapeutic potential. An increasing number of candidates applicable for therapy purpose have been identified from other helminths ( 136 ), specific examples being anti-inflammatory protein-2 (AIP-2) from hookworm ( 137 ) and EgKI-1, a potent Kunitz type protease inhibitor from Echinococcus granulosus ( 126 ); on this basis, one could speculate that the schistosome orthologs of these molecules would likely elicit similar therapeutic effects. In addition, if these and other orthologs can provide the requisite therapeutic efficacy, in-depth analysis of the underlying molecular regulatory mechanisms would follow.…”

Schistosoma japonicum SjE16.7 Protein Promotes Tumor Development via the Receptor for Advanced Glycation End Products (RAGE)

“…However, some parasites may also act as negative regulators of cancer. This includes the activation of NK cells and CD8 + T cells seen during Toxoplasma gondii infection and the pro-apoptotic effects of Trypanosoma cruzi infection as well as the Kunitz type protease inhibitor from Echinococcus granulosus , which was shown to induce tumor cell apoptosis in a mouse melanoma model ( 14 , 15 ).…”

Proteomic Analysis of the Venom of Jellyfishes Rhopilema esculentum and Sanderia malayensis

“…A previous study demonstrated that the potassium ion channel blockade function of Kunitz domain-containing peptides grants them the potential application as neuroprotective drugs [ 59 ]. In addition, Kunitz domain-containing proteins also show therapeutic potential in the treatment of cancer [ 60 ] and hereditary angioedema [ 61 ], attributed to their protease inhibition ability.…”